Background: Skull base defects and encephaloceles of the sinus and nasal cavities are routinely repaired endoscopically using a variety of materials including bone, cartilage, fascia, acellular dermal allografts, and xenografts, with high success rates. However, there is a paucity of data regarding the use of porcine small intestine submucosal (SIS) grafts for endoscopic dural repair. The purpose of the current study was to review outcomes using SIS grafts in the endoscopic reconstruction of skull base defects. Methods: Review of prospectively collected data regarding skull base defect repair using SIS was performed. Demographics, location, and size of skull base defect, method of repair, successful closure, and complications were recorded. Results: Over 4.5 years, 155 patients (mean age 49 years) underwent 170 primary skull base repairs using porcine SIS. Etiologies included tumor (76), spontaneous (51), trauma (37), and congenital (5). The majority of repairs were in combination with a nasoseptal flap (n = 113). Average defect size (length vs width) was 13 × 10.5 mm. Success rate on first attempt was 94.7% (161/170), and all defects were effectively sealed on subsequent endoscopic revision. The average follow-up was 77 weeks. Major postoperative complications, including recurrent cerebrospinal fluid (CSF) leak (9), meningitis (1), periorbital cellulitis (1), and invasive fungal sinusitis (1), occurred in 6.4% of individuals with no long-term sequelae. Conclusion: Use of porcine SIS dural graft was associated with excellent outcomes in this study and evidence presented here supports its routine use in the endoscopic closure of skull base defects. © 2013 ARS-AAOA, LLC.